HGG-05. PERTURBING GABAERGIC NEURONAL LINEAGE IN DIFFUSE HEMISPHERIC GLIOMA, H3G34-MUTANT, HIGHLIGHTS CDK6 AS A CLINICALLY ACTIONABLE TARGET
Authors: Ilon Liu, Gustavo Alencastro Veiga Cruzeiro, Lynn Bjerke, Rebecca Rogers, Yura Grabovska, Alexander Beck, Alan Mackay, Tara Barron, Olivia Hack, Michael Quezada, Valeria Molinari, McKenzie Shaw, Sara Temelso, Florence Raynaud, Ruth Ruddle, Eshini Panditharatna, Bernhard Englinger, Hafsa Mire, Li Jiang, Andrezza Do Nascimento Silva, Jenna LaBelle, Rebecca Haase, Jacob Rozowsky, Quang-De Nguyen, Giulia Pericoli, Sibylle Madlener, Lisa Mayr, Christian Dorfer, Rene Geyeregger, Gerda Ricken, Keith Ligon, Sanda Alexandrescu, Sameer Agnihotri, David Eisenstat, Fernando Carceller, Simon Stapleton, Cristina Bleil, Angela Mastronuzzi, Kristina Cole, Angela Waanders, Angel Montero Carcaboso, Ulrich Schüller, Maria Vinci, Darren Hargrave, Christine Haberler, Irene Slavc, Johannes Gojo, Michelle Monje, Chris Jones, Mariella Filbin
Journal: Neuro-Oncology (2023)

Abstract Diffuse hemispheric gliomas, H3G34R/V-mutant (DHG-H3G34), are uniformly lethal malignancies with currently no targeted therapies available. They exclusively occur in the cerebral hemispheres of adolescents and young adults, and have been linked to a distinct interneuronal lineage of origin. The developmental spectrum and functional role of this interneuronal lineage in DHG-H3G34 remain incompletely understood. Here, through integrating bulk and single-cell multi-omics with genome-wide CRISPR-Cas9 screens, we resolve a putative cellular hierarchy that follows a continuum of interneuronal lineage development, ranging from a self-renewing progenitor-like cell to a more differentiated cell resembling early immature GABAergic interneurons, along with quiescent astrocyte-like and mesenchymal-like cells. We validate these single-cell states in patient DHG-H3G34 tissue sections by multiplexed immunofluorescence, and describe spatial structures that resemble nests of early migratory interneurons surrounded by progenitor cells, characteristic of human embryonal interneuron development. Intriguingly, we reveal the majority of CRISPR-Cas9 screen-derived gene dependencies are upregulated in interneuronal lineage tumor cells, specifically in less differentiated progenitor-like cells, highlighting these as a driver of DHG-H3G34. We validate the essentiality of these interneuronal lineage associated targets in patient-derived in vitro and in vivo models, and highlight CDK6 as a druggable target selectively upregulated in DHG-H3G34. Inhibition of CDK6 leads to a decrease of undifferentiated progenitor-like signatures, reduced tumor growth, and prolonged survival of patient-derived xenograft models. Encouraged by these findings, we treated a patient upon a second relapse of a DHG-H3G34 with ribociclib on a compassionate use basis, who, as of the time of submission, has shown stable disease within four cycles of ribociclib treatment after progression on PCV chemotherapy. In sum, we reveal CDK6 inhibition as a rationally informed and clinically actionable therapeutic avenue that selectively perturbs the unique interneuronal lineage in DHG-H3G34, paving the way for rapid clinical translation.